In recent years much pharmacological research concerning .gamma.-aminobutyric acid (hereinafter designated GABA), an inhibitory neurotransmitter in the mammalian central nervous system, has been carried out.
The inhibition of GABA uptake results in enhanced availability of this inhibitory neurotransmitter in the synaptic cleft and thus to increased GABA' ergic activity. Increased GABA'ergic activity can be useful in the treatment, for example of anxiety, pain and epilepsy, as well as muscular and movement disorders (see, for example, P. Krogsgaard-Larsen et al., Progress in Medicinal Chemistry, 1985, 22, 68-112).
A well-known and potent inhibitor of GABA uptake from the synaptic cleft into presynaptic nerve terminals and glial cells is, for example, 3-piperidinecarboxylic acid (nipecotic acid). However, being a relatively polar compound and therefore unable to cross the blood-brain barrier, 3-piperidinecarboxylic acid itself has found no practical utility as a drug.
In U.S. Pat. No. 4,383,999 and No. 4,514,414 (SmithKline Beckman Corporation) and in EP 236342 as well as in EP 231996 (Novo Industri A/S) some derivatives of N-(4,4-disubstituted-3-butenyl)azaheterocyclic carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 and EP 374801 (Novo Industri A/S), N-substituted azaheterocyclic carboxylic acids in which an oxime ether group and vinyl ether group forms part of the N-substituent respectively are claimed as inhibitors of GABA uptake. EP 221572 (Warner-Lambert Company) claims that 1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.
In addition to the above cited references, U.S. Pat. No. 2,976,286 and British Patent No. 905,692 discloses 10-(dialkylaminoethoxyethyl)phenothiazines and U.S. Pat. No. 2,965,639 discloses 5-(dialkylaminoethoxyethyl)-10,11-dihydrodibenzo[b,f]azepines. The compounds of U.S. Pat. No. 2,965,639 and British Patent No. 905,692 are disclosed for having antihistaminic, spasmolytic, anti-inflammatory, sedative and ganglion-blocking activity. The compounds of the present invention essentially differ from the compounds in U.S. Pat. No. 2,976,286, U.S. Pat. No. 2,965,639 and British Patent No. 905,692 by the amino acid moiety important for the inhibition of GABA uptake.
According to Yunger, L. M. et al., J. Pharm. Exp. Ther. 1984, 228, 109, N-(4,4-diphenyl-3-buten-1-yl)nipecotic acid (designated SK&F 89976A), N-(4,4-diphenyl-3-buten-1-yl)guvacine (designated SK&F 100330A), N-(4,4-diphenyl-3-buten-1-yl)-homo-.beta.-proline (designated SK&F 100561) and N-(4-phenyl-4-(2-thienyl)-3-buten-1-yl)nipecotic acid (designated SK&F 100604J) are orally active inhibitors of GABA uptake. These data are summarized in Krogsgaard-Larsen, P. et al., Epilepsy Res. 1987, 1, 77-93.
Guvacine is 1,2,5,6-tetrahydropyridine-3-carboxylic acid and homo-.beta.-proline is pyrrolidine-3-acetic acid.